Escitalopram and solid pharmaceutical composition comprising the same

ABSTRACT

The present invention relates to Escitalopram having a small median particle size and a solid pharmaceutical composition comprising the same.

PRIORITY

This instant application is a continuation of U.S. Ser. No. 12/446,246filed Apr. 28, 2009, now U.S. Pat. No. ______, issued ______, which, inturn, corresponds to the national phase of International Application No.PCT/EP07/009,040, filed Oct. 18, 2007, which, in turn, claims priorityto Indian Patent Application No. 1931/CHE/2006, filed Oct. 20, 2006. Theentire contents of all priority applications are hereby incorporated byreference herein in their entirety.

TECHNICAL FIELD OF THE PRESENT INVENTION

The present invention relates to Escitalopram having a small medianparticle size and a solid pharmaceutical composition comprising thesame.

BACKGROUND OF THE PRESENT INVENTION

Escitalopram is the S-enantiomer of the antidepressant drug Citalopram,i.e.(S)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile.Citalopram has the following chemical structure:

Citalopram was first disclosed in DE 2 657 013 which also disclosesmethods for preparing this compound. The Citalopram prepared wasisolated in crystalline form as the oxalate, the hydrobromide and thehydrochloride salt, respectively. Citalopram is marketed as thehydrobromide.

Escitalopram, the pharmaceutical activity thereof and crystallineescitalopram oxalate are disclosed in U.S. Pat. No. 4,943,590. Methodsfor preparation of pharmaceutical preparations of Escitalopram are alsooutlined.

Citalopram is marketed in a number of countries as a tablet prepared byeither direct compression or compression of granulated citalopramhydrobromide, lactose and other excipients.

It is well recognized that the preparation of tablets with areproducible composition requires that all the dry ingredients have goodflow properties. In cases, where the active ingredient has good flowproperties, tablets can be prepared by direct compression of theingredients. However, in many cases the particle size of the activesubstance is small, the active substance is cohesive or has poor flowproperties. Furthermore, active substances with a small particle sizemixed with excipients having a larger particle size will typicallysegregate or de-mix during the tabletting process. The problem of smallparticle size and poor flowability is conventionally solved by enlargingthe particle size of the active substance, usually by granulation of theactive ingredient either alone or in combination with a filler and/orother conventional tablet ingredients. However, also granulation of theactive ingredient may be difficult if the flow behaviour is poor.Moreover, additional time and energy consuming and, thus, costlypreparation steps are required.

WO 2003/011278 aims at avoiding such problems by providing largercrystals of Escitalopram oxalate having a median particle size of atleast 40 μm via a novel crystallization process.

WO 2005/084643 discloses that crystalline particles of Escitalopramoxalate though having a smaller particle size as those disclosed in WO2003/011278 are nevertheless suitable for use in direct compression ifthey have a wide particle size distribution being defined in that theratio between the median particle size and the particle size at 95%quantile is less than 0.42. Nevertheless, the median particle size ofthe Escitalopram oxalate crystalline particles should be at least 20 μm.

Preparing Escitalopram particles having a relatively large particle sizeaccording to the method of WO 2003/011278 or a large particle sizedistribution according to WO 2005/084643 requires additional steps andefforts in the preparation method which therefore becomes more costly.Therefore, there is still a need for Escitalopram which can easily bemanufactured into solid pharmaceutical compositions and which can beobtained in an easy and cost efficient manner.

SUMMARY OF THE PRESENT INVENTION

It has now surprisingly been found that Escitalopram having a smallmedian particle size can nevertheless be easily formulated into solidpharmaceutical compositions if it has a narrow particle sizedistribution. Therefore, the present invention relates to Escitalopramor pharmaceutically acceptable salt and/or solvate thereof being in theform of particles having a median particle size of less than 40 μm,characterized in that the ratio between the median particle size and theparticle size at the 95% quantile is equal to or greater than 0.42.

Surprisingly it has been found that contrary to the disclosure of WO2003/011278 and WO 2005/084643 and the general knowledge of the personskilled in the art Escitalopram having a small particle size does notshow the expected disadvantages in flow behaviour and, thus,processability if it is provided as particles having a narrow particlesize distribution. In this case the active ingredient can be easilyhandled, mixed with excipients even having a larger particle size andcan be processed into pharmaceutical compositions such as tablets orcapsules without the known and expected problems such as segregation orde-mix during the processing steps. It is even possible to preparetablets by direct compression without the requirement or previousgranulation of the active ingredient into larger particles in order toincrease the flow properties. Likewise the granulation is possible aswell, because the flow behaviour of the Escitalopram of a small mediumparticle size and a narrow particle size distribution facilitates thegranulation process. Thus, it is possible to prepare pharmaceuticalcompositions with the Escitalopram of the present invention in a fastand cost efficient manner. It has also surprisingly been found that withEscitalopram being in the form of small particles and having theparticle size distribution of the present invention accurate dosing ofthe active ingredient and excipients into capsules is possible withoutthe expected problems, such as de-mix of the ingredients duringprocessing.

Due to its good flow properties Escitalopram of the present invention issuitable for the preparation of tablets by direct compression. Inparticular, it is not necessary to first prepare granules of the activeingredient with other excipients before compression of these granulesinto tablets.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 shows the dissolution profile of the commercially availableCipralex® tablets and Example 2.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

As used herein “direct compression” means that the solid unit dosageform is prepared by compression of a simple mixture of the activeingredient and excipients, without the active ingredient having beensubjected to an intermediate granulation process in order to imbed it ina larger particle and improve its fluidity properties.

Alternatively, the Escitalopram of the present invention can be used toprepare a premix with suitable excipients. This premix can then be usedin a granulation process or for filling capsules.

As used herein, “particle size distribution” means the cumulative volumesize distribution of equivalent spherical diameters as determined bylaser diffraction at 1 bar dispersive pressure in a Sympatec Helosequipment. “Median particle size”, correspondingly, means the median ofsaid particle size distribution. When the term “Escitalopram” is used itcovers Escitalopram as well as a pharmaceutically acceptable salt and/ora pharmaceutically acceptable solvate thereof.

Thus, in a first aspect the present invention relates to Escitalopram ora pharmaceutically acceptable salt and/or solvate thereof having amedian particle size of less than 40 μm and wherein the ratio betweenthe median particle size and the particle size at the 95% quantile isequal to or greater than 0.42. The Escitalopram may be in amorphous orcrystalline form, preferably it is in the form of crystalline particles.Preferably the median particle size is less than 20 μm, more preferablyless than 10 μm, and most preferably between 4 μm and 8 μm.

In order to achieve the unexpected good results of the present inventionthe Escitalopram must have a narrow particle size distribution beingdefined by the ratio between the median particle size and the particlesize at the 95% quantile. This ratio must be equal to or greater than0.42, preferably greater than 0.45, more preferably greater than 0.50and most preferably between 0.55 and 0.70, such as for example about0.60±0.02.

The Escitalopram preferably is present in the form of a pharmaceuticallyacceptable salt thereof. As pharmaceutically acceptable salts thehydrobromide, hydrochloride, and oxalate can be mentioned. The oxalatesalt of Escitalopram is preferred. The Escitalopram of the presentinvention is particularly suitable for the preparation of solidpharmaceutical compositions. Therefore, in a further embodiment thepresent invention relates to a solid pharmaceutical compositioncomprising Escitalopram or a pharmaceutically acceptable salt and/orsolvate thereof wherein the Escitalopram is in the form of particleshaving a median particle size of less than 40 μm, characterized in thatthe ratio between the median particle size and the particle size at the95% quantile is equal to or greater than 0.42.

Preferably, the solid pharmaceutical composition is in the form of atablet or capsule. The process for preparing the pharmaceuticalcomposition may comprise the step of direct compression, wet granulationand/or dry compaction.

The solid pharmaceutical composition according to the invention maycontain 1-60% by weight active ingredient calculated as Escitaloprambase, preferably 4-40% by weight active ingredient calculated asEscitalopram base. For example, the solid pharmaceutical composition inthe form of a unit dosage form may comprise 5 mg, 10 mg, 15 mg or 20 mgEscitalopram base.

The solid pharmaceutical composition of the present invention mayfurther comprise excipients, such as diluents, binders, disintegrants,glidants, lubricants, levigating agents and/or film coating agents. Asdiluents and binders mannitol, lactose, starch and microcrystallinecellulose can be exemplified. As disintegrants L-hydroxypropyl celluloseand crosscarmellose can be exemplified. As glidants talc and colloidalanhydrous silica can be exemplified. As lubricants talc and magnesiumstearate can be exemplified. As levigating agent glycerin can beexemplified. As film coating agents methylhydroxypropylcellulose andEudragit® can be exemplified.

Besides the above compounds the pharmaceutical composition of thepresent invention may comprise various other conventional excipients asknown to the person skilled in the art. Optionally minor amounts ofcolorants and sweeteners may also be present.

Optionally, the solid pharmaceutical composition of the presentinvention may be coated. Suitably the coating is a film coating based onconventional coating mixtures such as Opadry white 03B28796,manufactured by Colorcon.

The solid pharmaceutical composition of the present invention may beprepared by conventional methods as known to those skilled in the art.The tablets may be prepared by conventional tabletting methods. Thetablets can be prepared by direct compression without an intermediategranulation step. Alternatively, the tablets can be prepared bygranulating a premix comprising the Escitalopram of the presentinvention and one or more excipients, and forming the thus obtainedgranules into tablets. In a further embodiment the premix comprising theactive ingredient together with one or more excipients may be filledinto capsules, such as hard gelatine capsules by conventional methods,for example using a capsule filler suitable for powder filling. Thepremix preferably is in the form of a powder, in particular a drypowder.

Surprisingly, tablets prepared with Escitalopram oxalate of the presentinvention nevertheless exhibit a dissolution profile being very similarto the dissolution profile of the commercially available Cipralex®tablets. Preferably the pharmaceutical composition of the presentinvention is a bio equivalent solid dosage form for Cipralex®.

In a further aspect the present invention relates to the use ofEscitalopram or a pharmaceutically acceptable salt and/or solvatethereof as described above for the preparation of solid pharmaceuticalcompositions.

The following examples are merely intended to illustrate the inventionand should not be construed as limiting.

In the following examples Escitalopram oxalate having a median particlesize between of about 6.65 μm and a ratio between the median particlesize and the particle size at the 95% quantile of about 0.61 isemployed.

Example 1

Item Percentage No. Ingredients (%) Function 1. Escitalopram oxalate9.83% Active Pharmaceutical Ingredient 2. Pearlitol 200 SD 31.70% Diluent 3. Microcrystalline cellulose102 47.50%  Diluent 4. L-Hydroxypropyl cellulose LH21 3.00% Disintegrant 5. Colloidal silicon dioxide0.50% Glidant 6. Talc 5.00% Glidant/lubricant Lubrication 7. Magnesiumstearate 1.00% Lubricant Film coating 8. Opadry white 03B28796 1.50%Film Coating agent 9. Purified water q.s. Solvent Total Weight 100.0% (260.0 mg for 20 mg strength)

Process:

-   -   I. Weigh accurately all the above ingredients as per respective        quantity.    -   II. Mix item no. 2, 3, 4, and 5 and sift through #40 mesh.    -   III. Mix item no. 1 and item no. 6 and sift through #40 mesh.    -   IV. Mix step II with step III continue blending for adequate        time period and sift through #40 mesh.    -   V. Sift item no. 7 through #40 mesh.    -   VI. Lubricate the blend of step IV with sifted item of step V.    -   VII. Compress the blend of step VI as per specified parameters*.    -   VIII. Film coat the step VII core tablets with use of an        appropriate coating pan/machine with up to standard parameters.

*Compression Parameters:

Avg. wt. of core tablet: 256 mg±2%, Hardness: NLT 80 N

Avg. wt. of film coated tablet: 260 mg±2%.

This example involves direct compression, however is also suitable forwet granulation and for dry compaction.

Example 2

Item Percentage No. Ingredients (%) Function 1. Escitalopram oxalate9.83% Active Pharmaceutical Ingredient 2. Pharmatose DCL21 29.19% Diluent 3. Microcrystalline cellulose 102 50.00%  Diluent 4. L-Hydroxypropyl cellulose LH21 3.00% Disintegrant 5. Colloidal silicon dioxide0.50% Glidant 6. Talc 5.00% Glidant/lubricant Lubrication 7. Magnesiumstearate 1.00% Lubricant Film coating 8. Opadry white 03B28796 1.50%Film Coating agent 9. Purified water q.s. Solvent Total Weight 100.0% (260.0 mg for 20 mg strength)

Process:

-   -   I. Weigh accurately all the above ingredients as per respective        quantity.    -   II. Mix item no. 2, 3, 4, and 5 and sift through #40 mesh.    -   III. Mix item no. 1 and item no. 6 and sift through #40 mesh.    -   IV. Mix step II with step III continue blending for adequate        time period and sift through #40 mesh.    -   V. Sift item no. 7 through #40 mesh.    -   VI. Lubricate the blend of step IV with sifted item of step V.    -   VII. Compress the blend of step VI as per specified parameters*.    -   VIII. Film coat the step VII core tablets with use of an        appropriate coating pan/machine with up to standard parameters.

*Compression Parameters:

Avg. wt. of core tablet: 256 mg±2%, Hardness: NLT 80 N

Avg. wt. of film coated tablet: 260 mg±2%.

This example involves direct compression, however is also suitable forwet granulation and for dry compaction.

Example 3

Item Percentage No. Ingredients (%) Function Process (DirectCompression) 1. Escitalopram oxalate 9.83% Active PharmaceuticalIngredient 2. Starch 1500 15.84%  Diluent/Binder 3. Microcrystallinecellulose102 63.35%  Diluent 4. L-Hydroxy propyl cellulose LH21 3.00%Disintegrant 5. Colloidal silicon dioxide 0.50% Glidant 6. Talc 5.00%Glidant/lubricant Lubrication 7. Magnesium stearate 1.00% Lubricant Filmcoating 8. Opadry white 03B28796  1.5% Film Coating agent 9. Purifiedwater q.s. Solvent Total Weight  100% (260.0 mg for 20 mg strength)

Process:

-   -   I. Weigh accurately all the above ingredients as per respective        quantity.    -   II. Mix item no. 2, 3, 4, and 5 and sift through #40 mesh.    -   III. Mix item no. 1 and item no. 6 and sift through #40 mesh.    -   IV. Mix step II with step III continue blending for adequate        time period and sift through #40 mesh.    -   V. Sift item no. 7 through #40 mesh.    -   VI. Lubricate the blend of step IV with sifted item of step V.    -   VII. Compress the blend of step VI as per specified parameters*.    -   VIII. Film coat the step VII core tablets with use of an        appropriate coating pan/machine with up to standard parameters.

*Compression Parameters:

Avg. wt. of core tablet: 256 mg±2%, Hardness: NLT 80 N

Avg. wt. of film coated tablet: 260 mg±2%.

This example involves direct compression, however is also suitable forwet granulation and for dry compaction.

Example 4

Item Percentage No. Ingredients (%) Function Process (DirectCompression) 1. Escitalopram oxalate 9.83% Active PharmaceuticalIngredient 2. Starch 1500 15.84%  Diluent/Binder 3. Pearlitol 200 SD63.35%  Diluent 4. L-Hydroxy propyl cellulose LH21 3.00% Disintegrant 5.Colloidal silicon dioxide 0.50% Glidant 6. Talc 5.00% Glidant/lubricantLubrication 7. Magnesium stearate 1.00% Lubricant Film coating 8. Opadrywhite 03B28796 1.50% Film Coating agent 9. Purified water q.s. SolventTotal Weight 100.0%  (260.0 mg for 20 mg strength)

Process:

-   -   I. Weigh accurately all the above ingredients as per respective        quantity.    -   II. Mix item no. 2, 3, 4, and 5 and sift through #40 mesh.    -   III. Mix item no. 1 and item no. 6 and sift through #40 mesh.    -   IV. Mix step II with step III continue blending for adequate        time period and sift through #40 mesh.    -   V. Sift item no. 7 through #40 mesh.    -   VI. Lubricate the blend of step IV with sifted item of step V.    -   VII. Compress the blend of step VI as per specified parameters*.    -   VIII. Film coat the step VII core tablets with use of an        appropriate coating pan/machine with up to standard parameters.

*Compression Parameters:

Avg. wt. of core tablet: 256 mg±2%, Hardness: NLT 80 N

Avg. wt. of film coated tablet: 260 mg±2%.

This example involves direct compression, however is also suitable forwet granulation and for dry compaction.

Example 5

Item Percentage No. Ingredients (%) Function Process (DirectCompression) 1. Escitalopram oxalate 9.83% Active PharmaceuticalIngredient 2. Starch 1500 15.00%  Diluent/Binder 3. Pearlitol 200 SD63.19%  Diluent 4. Glycerin 1.00% Levigating agent 5. L-Hydroxy propylcellulose LH21 3.00% Disintegrant 6. Colloidal silicon dioxide 0.50%Glidant 7. Talc 5.00% Glidant/lubricant Lubrication 8. Magnesiumstearate 1.00% Lubricant Film coating 9. Opadry white 03B28796 1.50%Film Coating agent 10.  Purified water q.s. Solvent Total Weight 100.0% (260.0 mg for 20 mg strength)

Process:

-   -   I. Weigh accurately all the above ingredients as per respective        quantity.    -   II. Mix item no. 2, 3, 5, and 6 and sift through #40 mesh.    -   III. Levigate item no. 1 by item no. 4    -   IV. Mix step III and item no. 6 and sift through #40 mesh.    -   V. Mix blend of step II with blend of step III continue blending        for adequate time period and sift through #40 mesh.    -   VI. Sift item no. 7 through #40 mesh.    -   VII. Lubricate the blend of step IV with sifted item of step V.    -   VIII. Compress the blend of step VI as per specified        parameters*.    -   IX. Film coat the step VII core tablets with use of an        appropriate coating pan/machine with up to standard parameters.

*Compression Parameters:

Avg. wt. of core tablet: 256 mg±2%, Hardness: NLT 80 N

Avg. wt. of film coated tablet: 260 mg±2%.

This example involves direct compression, however is also suitable forwet granulation and for dry compaction.

Example 6

Item Percentage No. Ingredients (%) Function 1. Escitalopram oxalate9.83% Active Pharmaceutical Ingredient 2. Microcrystalline cellulose PH101 40.00%  Diluent 3. Lactose Monohydrate 25.79%  Diluent 4.Crosscarmellose sodium 2.70% Disintegrant 5. Maize starch 5.00% Binder6. Glycerol 0.35% Co-solvent 7. Purified water q.s. SolventExtra-granular 8. Copovidone 2.61% Binder 9. Crosscarmellose sodium2.00% Disintegrant 10. Maize starch 0.96% Disintegrant 11.Microcrystalline cellulose PH 101 7.76% Anti-adherent/ disintegrantLubrication 12. Magnesium stearate 1.00% Lubricant Film coating 13.Opadry white 03B28796 2.00% Film Coating agent 14. Purified water q.s.Solvent Total Weight (260.0 mg for 20 mg strength) 100.0% 

Process:

-   -   I. Weigh accurately all the above ingredients as per respective        quantity.    -   II. Mix item no. 1, 2, 3 and 4 and sift through #40 mesh.    -   III. Prepare paste with item no. 7, 6, and 5    -   IV. Granulate step II in an appropriate granulator.    -   V. Dry step V as to get up to standard loss of drying (%) and        sift through #30 mesh.    -   VI. Mix item no. 8, 9, 10 and 11 and sift though #30 mesh.    -   VII. Mix step VI with step V.    -   VIII. Sift item no. 12 through #40 mesh.    -   IX. Lubricate the blend of step VII with sifted item of step        VIII.    -   X. Compress the blend of step IX as per specified parameters*.    -   XI. Film coat the step X core tablets with use of an appropriate        coating pan/machine with up to standard parameters.

*Compression Parameters:

Avg. wt. of core tablet: 256 mg±2%, Hardness: NLT 80 N

Avg. wt. of film coated tablet: 260 mg±2%.

Example 7

Item Percentage No. Ingredients (%) Function Process (DirectCompression) 1. Escitalopram oxalate 9.83% Active PharmaceuticalIngredient 2. Prosolv SMCC HD 90 79.07%  Diluent/Binder 3.Crosscarmellose sodium 3.60% Diluent 4. Talc 5.00% Glidant/lubricantLubrication 5. Magnesium stearate 1.00% Lubricant Film coating 6. Opadrywhite 03B28796 1.50% Film Coating agent 7. Purified water q.s. SolventTotal Weight 100.0%  (260.0 mg for 20 mg strength)

Process:

-   -   I. Weigh accurately all the above ingredients as per respective        quantity.    -   II. Mix item no. 2 and 3 and sift through #40 mesh.    -   III. Mix item no. 1 and item no. 4 and sift through #40 mesh.    -   IV. Mix step II with step III continue blending for adequate        time period and sift through #40 mesh.    -   V. Sift item no. 5 through #40 mesh.    -   VI. Lubricate the blend of step IV with sifted item of step V.    -   VII. Compress the blend of step VI as per specified parameters*.    -   VIII. Film coat the step VII core tablets with use of an        appropriate coating pan/machine with up to standard parameters.

*Compression Parameters:

Avg. wt. of core tablet: 256 mg±2%, Hardness: NLT 80 N

Avg. wt. of film coated tablet: 260 mg±2%.

This example involves direct compression, however is also suitable forwet granulation and for dry compaction.

Example 8

In this example the dissolution profiles of the tablets obtained byabove Example 2 and the commercially available Cipralex® tablets aremeasured. The dissolution rates were measured in 900 ml of 0.1 M HClusing an USP Type II apparatus at 75 rpm. The results are summarized inthe following table 1.

TABLE 1 dissolution dissolution rate [%] rate [%] Time [min] Cipralex ®Example 2 0 0 0 5 99.72 98.54 10 100.32 98.72 15 101.24 98.73 30 102.2399.04 45 103.15 99.05

The results are also shown in enclosed FIG. 1.

The above example demonstrates that the tablets prepared according tothe present invention have a dissolution profile being very similar tothe dissolution profile of the commercially available Cipralex® tablets.

1. A solid pharmaceutical composition comprising Escitalopram or apharmaceutically acceptable salt thereof in the form of particles havinga median particle size of less than 20 μm, characterized in that theratio between the median particle size and the particle size at the 95%quantile is greater than 0.42.
 2. The solid pharmaceutical compositionaccording to claim 1 being in the form of a tablet or capsule.
 3. Thesolid pharmaceutical composition according to claim 2 being in the formof a tablet obtained by direct compression.
 4. The solid pharmaceuticalcomposition according to claim 2 being in the form of a tablet obtainedby a process comprising a step of wet granulation or dry compaction. 5.The solid pharmaceutical composition according to claim 1, wherein theparticles have a median particle size of less than 10 μm.
 6. The solidpharmaceutical composition according to claim 1, wherein the particleshave a median particle size between 4 μm and 8 μm.
 7. The solidpharmaceutical composition according to claim 1, wherein the ratiobetween the median particle size and the particle size at 95% quantileis greater than 0.50.
 8. The solid pharmaceutical composition accordingto claim 1, wherein the ratio between the median particle size and theparticle size at 95% quantile is between 0.55 and 0.70.
 9. The solidpharmaceutical composition according to claim 1, wherein theEscitalopram is in the form of an oxalate salt.
 10. A premix forpreparing a pharmaceutical composition, wherein said premix comprisesEscitalopram or a pharmaceutically acceptable salt thereof in the formof particles having a median particle size of less than 20 μm,characterized in that the ratio between the median particle size and theparticle size at the 95% quantile is greater than 0.42, in combinationwith one or more excipients.